Department of Pediatrics, Kumamoto Takumadai Rehabilitation Hospital, Kumamoto, Japan.
Data Science Center for Medicine and Hospital Management, Toyama University Hospital, Toyama, Japan.
Neuropathology. 2024 Dec;44(6):411-421. doi: 10.1111/neup.12995. Epub 2024 Jul 16.
Dystrophinopathy is caused by alterations in the dystrophin gene. The severe phenotype, Duchenne muscular dystrophy (DMD), is caused by a lack of dystrophin in skeletal muscles, resulting in necrosis and regenerating fibers, inflammatory cells, and muscle fibrosis. Progressive muscle weakness is a characteristic finding of this condition. Here, we encountered a rare case of a 10-year-old patient with asymptomatic dystrophinopathy with no dystrophin expression and investigated the reason for the absence of muscle weakness to obtain therapeutic insights for DMD. Using RNA-seq analysis, gene expression in skeletal muscles was compared among patients with asymptomatic dystrophinopathy, three patients with typical DMD, and two patients without dystrophinopathy who were leading normal daily lives. Cathepsin K (CTSK), myosin heavy chain 3 (MYH3), and nodal modulator 3-like genes exhibited a >8-fold change, whereas crystallin mu gene (CRYM) showed a <1/8-fold change in patients with typical DMD compared with their expression in the patient with asymptomatic dystrophinopathy. Additionally, CTSK and MYH3 expression exhibited a >16-fold change (P < 0.01), whereas CRYM expression showed a <1/16-fold change (P < 0.01) in patients with typical DMD compared with their expression in those without dystrophinopathy. CTSK plays an essential role in skeletal muscle loss, fibrosis, and inflammation in response to muscles injected with cardiotoxin, one of the most common reagents that induce muscle injury. Increased CTSK expression is associated with muscle injury or necrosis in patients with DMD. The lack of muscle weakness in the patient with asymptomatic dystrophinopathy might be attributed to the low CTSK expression in the muscles. To the best of our knowledge, this is the first report to demonstrate that CTSK expression was significantly higher in the skeletal muscles of patients with DMD with a typical phenotype than in those without dystrophinopathy.
肌营养不良症是由 dystrophin 基因突变引起的。严重表型，杜氏肌营养不良症（DMD），是由于骨骼肌中缺乏肌营养不良蛋白，导致坏死和再生纤维、炎症细胞和肌肉纤维化。进行性肌肉无力是这种情况的特征性发现。在这里，我们遇到了一例罕见的 10 岁无症状肌营养不良症患者，该患者没有肌营养不良蛋白表达，并研究了肌肉无力缺失的原因，以期为 DMD 获得治疗启示。使用 RNA-seq 分析，比较了无症状肌营养不良症患者、3 名典型 DMD 患者和 2 名无肌营养不良症但生活正常的患者的骨骼肌中的基因表达。与无症状肌营养不良症患者相比，典型 DMD 患者的组织蛋白酶 K（CTSK）、肌球蛋白重链 3（MYH3）和节点调节剂 3 样基因的表达变化超过 8 倍，而晶状体 mu 基因（CRYM）的表达变化则小于 1/8 倍。此外，与无肌营养不良症患者相比，典型 DMD 患者的 CTSK 和 MYH3 表达变化超过 16 倍（P<0.01），而 CRYM 表达变化则小于 1/16 倍（P<0.01）。CTSK 在心肌毒素（一种最常诱导肌肉损伤的试剂之一）注射引起的骨骼肌丢失、纤维化和炎症中发挥重要作用。在 DMD 患者中，CTSK 表达增加与肌肉损伤或坏死有关。无症状肌营养不良症患者的肌肉无力缺失可能归因于肌肉中 CTSK 表达较低。据我们所知，这是第一个表明 CTSK 表达在典型表型的 DMD 患者的骨骼肌中明显高于无肌营养不良症患者的报告。
